The present invention relates to a process for the preparation of thieno[3,2-c]pyridine derivatives of general formula (I), in either racemic or optionally active (+) or (xe2x88x92) forms and their salts, wherein X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. 
Preferably, X represents 2-chloro.
The present invention also describes a process for preparing the compounds of general formula (II), in either racemic or optically active (+) or (xe2x88x92) forms and their salts, where X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. 
Preferably X represents 2-chloro. These compounds are useful intermediates to prepare compounds of general formula (I).
The compounds represented by formulae (I) and (II) have one asymmetric carbon and hence, to obtain optically active compounds of formula (I) or of formula (II), option available is either to resolve the racemic intermediate/final product or use an optically active intermediate.
Thieno[3,2-c]pyridine derivatives disclosed in FR 2,215,948, FR 2,530,247 and FR 2,612,929, are pharmacologically active and have significant anti-aggregating and anti-thrombotic properties. One such example is xe2x80x98Clopidogrelxe2x80x99, (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) acetic acid methyl ester and its pharmaceutically acceptable salts. Later, it was found that the biological activity resides only with (S)-(+)stereoisomer (U.S. Pat. No. 4,847,265). As xe2x80x98Clopidogrel basexe2x80x99 is an oily liquid, in order to prepare a convenient formulation, the base is converted into a pharmaceutically acceptable salt. Suitable salts of xe2x80x98Clopidogrel basexe2x80x99 can be formed with taurocholate, hydrobromide and sulfuric acid.
The reported methods to synthesize the compounds of general formula (I) (U.S. Pat. No. 4,529,596, GB 0420706 and GB 0466569), use xcex1-halophenylacetic acid derivatives, which are lacrimatory and irritant in nature. The processes to synthesize such compounds involve multiple steps, and have other drawbacks due to the chemicals/reagents used, which usually are difficult to handle, scale-up and unfavorable from human health as well as environmental point of view. Moreover, overall yields of these processes range from poor to average. Various other synthetic approaches found in literature, involve expensive or hazardous chemicals, which do not significantly improve the yield of the desired product.
Recently, radiolabelled (bezene-U-13C) racemic(xc2x1)-Clopidogrel has been prepared as a standard for metabolic studies in an overall yield of 7% using orthometalation/chlorination of benzoic acid derivative (Chem. Abst, 133:281711, 2000). Various other strategies are disclosed in: WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, U.S. Pat. Nos. 4,876,362, 5,036,156, 5,132,435, 5,139,170, 5,204,469 and 6,080,875.
Recently, a new polymorph of Clopidogrel bisulfate (named as form II) has been disclosed in patent application (WO 99/65915), which has a melting point of 176xc2x13xc2x0 C. It also mentions that the compound disclosed in the earlier US patent (U.S. Pat. No. 4,847,265), had a different melting point of about 184xc2x13xc2x0 C. (now referred as, form I). It has been shown that both the polymorphs have distinct and characteristic XRD and IR spectrum.
Consequently, the present invention aims to provide an inexpensive and commercially viable process to prepare compounds of formula (I) in good yields.
The main object of the present invention is to provide a novel process to prepare thieno[3,2-c]pyridine derivatives, represented by the general formula (I), in either racemic or optically active (+) or (xe2x88x92) forms and their salts, wherein X represents either hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. 
Another the object of the present invention is to provide a novel process to prepare thieno[3,2-c]pyridine derivatives, represented by the general formula (I), in either racemic or optically active (+) or (xe2x88x92) forms and their salts, through a commercially viable route.
A particular object of the present invention is to provide a novel process to manufacture (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester as bisulfate salt, i.e. Clopidogrel bisulfate, where X is 2-chloro substituent. 
The preferred object of the present invention is to provide a novel process to manufacture Clopidogrel bisulfate, through a commercially viable process.
Another important object of the present invention is to provide a novel process to manufacture polymorph form I of Clopidogrel having melting point 184xc2x13xc2x0 C., through commercially viable route.
Yet another object of the present invention is to recycle through a novel process the laevoisomer of Clopidogrel or a variable mixture of (+) and (xe2x88x92) stereoisomers to make (+)-Clopidogrel bisulfate.
Another object of the present invention is to provide a process to prepare a compound (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide of formula (A), either in racemic or as optically active (+) or (xe2x88x92) forms and their salts. 
Another object of the present invention is to provide a process for the preparation of a compound of formula (I) where X is 2-chloro, in racemic as well as optically active (+) or (xe2x88x92) forms having suitable chemical and chiral purity and along with their salts. The dextro isomer of compound with formula (II) with suitable purity or its salts, are useful intermediates for the synthesis of (+)-Clopidogrel bisulfate.
Still another object of the present invention is to provide a novel process to convert (R)-(xe2x88x92)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide or its mixture with variable minor amounts of its optical antipode, into almost a 1:1 mixture of (+) and (xe2x88x92) isomer.
It is also an object of the present invention is to provide a process to prepare compound of formula (III), (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid, in racemic (xc2x1) or in either of the optically active (+) or (xe2x88x92) form, and their salts.
Still another object of the present invention is to provide a novel process to convert (R)-(xe2x88x92)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid in a mixture to (S)-(+) stereoisomer.
Another object of the present invention is to provide a process for the preparation of a compound of formula (IV), (xc2x1)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile, and their salts.
Still another object of the present invention is to provide a novel process to convert (R)-(xe2x88x92)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile or its mixture with variable minor amounts of its optical antipode, into almost a 1:1 mixture of (+) and (xe2x88x92) isomer.
The process described herein provides a simple and alternative method to prepare compounds of the general formula (I), particularly (S)-(+)Clopidogrel bisulfate, polymorph form I.
The above and other objects of the present invention are achieved by the process of the present invention by employing compounds of formula (II) 
or its salts, in either racemic or optically active (+) or (xe2x88x92) forms, as outlined in Scheme 1.
Optionally, the present invention provides a method to resolve (xe2x88x92)-2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide into optically active (+) or (xe2x88x92) forms, which can be used to prepare (+)-Clopidogrel bisulfate.
Optionally, the present invention provides a method to resolve (xc2x1)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid into optically active (+) or (xe2x88x92) forms.
Optionally, the present invention provides a method to resolve (xc2x1)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile into optically active (+) or (xe2x88x92) forms
Accordingly, the present invention provides a process to prepare compounds of formula (I), in either racemic or optically active (+) or (xe2x88x92) forms and their salts, where X represents either hydrogen or a halogen atom such as fluorine, chlorine, bromine or iodine. More particularly, the present invention provides a process to prepare Clopidogrel bisulfate.
The process to prepare compounds of formula (I) or its salts, uses compounds of formula (II) 
or its salts, in either racemic or optically active (+) or (xe2x88x92) forms, as outlined in Scheme 1. 
Each intermediate in Scheme 1 has one chiral center. Hence, to prepare an optically active product, such as compound represented by formula (I), particularly Clopidogrel and its salt, it is possible to use an optically active intermediate from the first step onwards.
The present invention provides a process for the preparation of compounds of formula (I) and their salts as shown in scheme 1, which comprises:
1. preparing compound of formula (IV), (xc2x1)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile as described in Scheme 2, i.e. via Strecker reaction;
2. resolving, if desired, the racemic mixture of compound of formula (IV) into its optically active (+) and (xe2x88x92) stereoisomers; and recycling the unwanted stereoisomer into the process by racemization;
3. transforming the compound of formula (IV) in either racemic or optically active (+) or (xe2x88x92) form or its salt, into the compound of formula (II), (xc2x1)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide or optically active corresponding (+) or (xe2x88x92) form, based upon starting material used;
4. resolving, if desired, the racemic compound of formula (II)xe2x80x94into its optically active (+) and (xe2x88x92) stereoisomers; and recycling the unwanted stereoisomer into the process by racemization;
5. transforming the compound of formula (II), either in racemic or optically active (+) and (xe2x88x92) form or its salt, into either optically active or racemic compound of formula (I), (xc2x1)-(2-chloro phenyl) (6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester, in racemic or optically active (+) and (xe2x88x92) form and its salt, based upon starting material used;
6. further resolving and/or transforming the racemic/optically active compound of formula (I) into their pharmaceutically acceptable salts and/or, liberating the racemic or optically active compound of formula (I) from its salts.
Alternatively, either of the compounds of formulae (IV) or (II), either racemic or optically active (+) or (xe2x88x92) form can be transformed into corresponding compounds of formula (III); which can then be converted into corresponding compound of formula (I).
The compound of formula (IV) in racemic or optically active (+) or (xe2x88x92) forms can be directly converted into corresponding compound of formula (I).
Optionally, suitable acid addition salts of the intermediates of formula II, III and IV may be used in the above mentioned processes. Suitable acids used may be selected from acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, camphor sulfonic, hydrochloric, sulfuric, hydrobromic acids and the like.
Another aspect of the present invention is to provide a process for the preparation of a novel intermediate of formula (IV) and its salts. 
Yet another aspect of the process of invention includes preparation of intermediate described by general formula (IV) and as depicted in the Scheme 2, by Strecker reaction, using a secondary amine (Organic Synthesis Collective Volume III, page no. 275). 
The process to prepare compounds of formula (IV) includes, reacting amine of formula (V) or its salt, with a cyanide derivative of the general formula (VII), wherein M represents either alkali metals such as Na, K, Li, or H, trimethylsilyl (TMS) and the like; with 2-chlorobenzaldehyde of formula (VI). The synthesis of amine or its salt having formula (V) is described in FR 2608607.
The above reaction can be carried out in various ways. A few such methods are outlined in Scheme 2 shown above. Initially, amine of formula (V), or its salt, is reacted with cyanide (VII), wherein M is as defined earlier, followed by addition of 2-chlorobenzaldehyde (VI). Alternatively, 2-chlorobenzaldehyde (VI) is treated with cyanide of formula (VII), wherein M is as defined earlier, and the intermediate cyanohydrin is further reacted with amine of formula (V) or its salt. In an alternative method, 2-chlorobenzaldehyde of formula (VI) is added to hydrogen sulfite derivative of formula (VIII) wherein Mxe2x80x2 represents Na, K, Li and the like; followed by reaction with cyanide of formula (VII), wherein M is as defined earlier, and finally amine of formula (V) or its salt in an in situ reaction. Irrespective of the variations in the reaction methodology, the yield of resultant intermediate (IV) obtained is comparable.
The preferred method involves, addition of 2-chlorobenzaldehyde of formula (VI) to hydrogen sulfite derivative of formula (VIII). The salt formed is treated with cyanide of formula (VII), and finally with an amine of formula (V) or its salt in presence of suitable reagent and solvents.
Suitable reagents includes acid catalysts, such as glacial acetic acid (Synthesis, 1989, 616-618), hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, polyphosphoric acid and the like.
Suitable solvents can be hydrophilic solvents, either protic or aprotic, includes water, (C1-C4) alcohol, tetrahydrofuran, dimethyl formamide, DMSO, dioxane, 1,2-dimethoxyethane, acetic acid, propionic acid and the like, or a mixture of solvents thereof. The preferred solvent is a mixture of solvents and water in varying ratio. The more preferred reaction medium includes a mixture containing water and (C1-C4)alcohol in a ratio varying between 1:1 and 1:10.
When the reaction is carried out in aprotic or hydrophobic solvent, a phase transfer catalyst and a biphasic solvent system is necessary. Suitable phase transfer catalyst used in such a case may be tetrabutyl ammonium halide, benzyltrimethylammonium halide, and the like.
During the reaction, certain additives may be added. Such suitable additives may be cyclo[(S)-histidine-(S)phenyl alanine] and the like.
The reaction temperature may range from xe2x88x9230xc2x0 C. to reflux temperature of the solvent(s) used. The preferred temperature ranges from 0xc2x0 C. to 100xc2x0 C., and more preferably, from 40xc2x0 C. to 80xc2x0 C. However, when HCN (g) (Scheme 2, Intermediate VII, M=H) is used the required temperature is in the range of about xe2x88x9230xc2x0 C. to xe2x88x9210xc2x0 C.
This reaction may be carried out in the absence or presence of an inert atmosphere such as N2, He or Ar. The duration of the reaction may vary from 1 hrs to 3 days, more specifically 2 hrs to 2 days.
It is preferable to react a compound of formula (V), hydrogen sulfite derivative (VIII), and cyanide derivative (VII) with respect to 2-chloro benzaldehyde (VI) in the ratio preferably between 1 to 1.2 equivalents. The racemic cyano compound (IV) thus obtained, can be resolved into optically active (+) and (xe2x88x92) forms.
The cyano compound (IV) thus obtained can be converted into corresponding acid of formula (III), amide of formula (II) or acid of formula (I) as shown in Scheme 1 (R. C. Larrock, in xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, John Wiley and Sons, Inc, 1999, 2nd Ed., 815-818 and references therein).
Yet, another aspect of the present invention is to convert these intermediates II and III, into compounds of formula I, as shown in scheme 1. Each of (xc2x1), (+) or (xe2x88x92) the isomer of intermediate of formulae II and III, can be converted into the corresponding isomer of compounds of formula I.
The preferred route to obtain the compound of formula (I), involves conversion of either (xc2x1), (+) or (xe2x88x92) isomer cyano compound (IV) and its salts, into amide compound of formula (II), in the presence of suitable acids/base reagents in suitable solvents. Later resolving the amide into optically active (+) or (xe2x88x92) form or its salt and the optically active amide is being converted into optically active ester of formula (I) in presence of suitable catalyst and reagent.
The reaction to convert cyano compound of formula (IV) into amide compound of formula (II) may be carried out in presence of reagents, which include acid or a base. Suitable acids which may be used are, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, chloroacetic acid and the like or anhydrous alcoholic or aqueous solution of mineral acids such as sulfuric acid, HCl, HBr and the like. A base is preferred whenever the starting material is a racemic mixture. Suitable base which may be used are lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or mixtures thereof, preferably alkali metal hydroxides. Along with alkali metal hydroxides, excess of hydrogen peroxides or metal peroxides may also be used in the above reaction. Suitable solvent/s for the above reaction may be aqueous, polar or protic solvents such as water, (C1-C4)alcohol, acetone, acetic acid, dimethyl formamide, THF, DMSO, dioxane, DME and the like or mixtures thereof; preferably solvent consists of water, methanol or tert-BuOH or mixture of these solvents, in a ratio varying between 1:1 to 1:10.
The temperature ranges from 20xc2x0 C. to 250xc2x0 C., preferably, from 50xc2x0 C. to 150xc2x0 C. The reagents used in the above process can be in the range from 0.01 to 1.2 moles equivalents. The reaction may be carried out in the absence or presence of an inert atmosphere such as N2, He or Ar. The reactions under the basic conditions are preferably under inert atmosphere. The duration of reaction may range from xc2xd hr to 5 days, preferably from 2 hrs to 2 days.
The amide of formula (II), in either racemic or optically active (+) or (xe2x88x92) form, or their salt, can be converted to corresponding methyl ester of formula (I), in presence of at least one equivalent of methanol and acid, in suitable solvent.
Suitable acids which can be used include acetic acid, polyphosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, chloroacetic acid, or mineral acids, which includes, sulfuric acid, HCl, HBr and the like, which could be in different forms like acid dissolved in alcohol, anhydrous acids dissolved or saturated in alcohol and alcohol used may be methanol. The preferable acid is concentrated sulfuric acid in the 1 to 50 equivalent ratio. Suitable solvents for the above transformation may be polar or protic solvent such as hydrophilic solvents including methanol, acetone, acetic acid, THF, DMSO, dioxane, DME and the like or mixtures thereof. The preferable solvent consists of methanol at least in one equivalent and may be in large excess such that it acts as a solvent. Sometimes inert cosolvent, such as toluene, xylene etc. can also be used.
The temperature ranges from 20xc2x0 C. to 250xc2x0 C., preferably from 50xc2x0 C. to 150xc2x0 C. The reaction may be carried out in the absence or presence of an inert atmosphere such as N2, He or Ar. The duration of reaction may range from 3 hrs to 5 days, preferably from 4 hrs to 2 days.
It is possible to convert compound of formula (IV) in either racemic or optically active (+) or (xe2x88x92) form or its salt is converted into the corresponding acetic acid derivative of formula (III) in presence of suitable solvent and reagent. Suitable solvent/s may be aqueous or alcoholic in nature. Suitable reagents for the above reaction include acids as well as bases.
It is also possible to convert the cyano compound of formula (IV) in either racemic or optically active (+) or (xe2x88x92) form or its salts, directly into methyl ester of formula (I), in presence of at least one equivalent of acid and at least one equivalent of methanol in suitable solvents according to methods known in the literature.
The acid of formula (III) in either racemic or optically active (+) or (xe2x88x92) form or its salts can be converted into corresponding methyl ester of formula (I), in presence of suitable reagent in suitable solvents and at least one equivalent of methanol.
Suitable reagent which can be used include, thionyl chloride, acid chlorides such as pivaloyl chloride, alkylchloroformates like ethyl or methyl chloroformates and other such reagents which activate the COOH group, in a 1:1 equivalent ratio. Suitable solvent for the above transformations may be polar or protic solvent such as, methanol, acetone, dimethylformamide, THF, DMSO, dichloromethane, dichloroethane, dioxane, DME and the like or mixtures thereof. The preferable solvent consists of methanol in at least one equivalent and may be in large excess such that it acts as a solvent. The temperature ranges from 20xc2x0 C. to 250xc2x0 C., preferably from 50xc2x0 C. to 150xc2x0 C.
The reagents used in above process may range from 0.01 moles to equimolar ratios. The reaction may be carried out in the absence or presence of an inert atmosphere such as N2, He or Ar. The duration of reaction may range from 3 hours to 5 days, preferably from 3 hr to 2 days.
This manufacturing process to prepare the compounds of general formula (I) as shown in scheme 1, has following advantages:
1) It requires less number of steps to prepare the compounds of the formula (I).
2) Simple readily available reagents/chemicals are used.
3) Milder reaction conditions are employed in various steps.
4) It is possible to get chiral/optically active intermediates at every stage (I, II, III or IV)
5) It is possible to racemize the unwanted isomers thereby enhancing efficiency and reducing environmental load.
6) The above factors contribute to improve cost effectiveness of the process described herein.
The compounds of the formulae (I), (II), (III) and (IV) can be resolved by various methods to get optically active compounds of the formulae (I), (II), (III) and (IV), which can give Clopidogrel of desired stereochemistry (R. A. Sheldon, in xe2x80x9cChirotechnologyxe2x80x9d, Marcel Dekker, Inc. NY, Basel, 1993, 173-204 and references therein; A. N. Collins, G. N. Sheldrack and J Crosby, in xe2x80x9cChirality in Industry IIxe2x80x9d, John Wiley and Sons, Inc, 1997, 81-98 and references therein; E. L. Eliel and S. H. Wilen, in xe2x80x9cStereochemistry of Organic Compoundxe2x80x9d, John Wiley and Sons, Inc, 1999, 297-464 and references therein).
The process of resolution comprises of dissolving the racemic mixture (of formulae I, II, III or IV) in suitable solvent and addition of a suitable chiral reagent. Optionally the medium may contain water about  less than 5%. Suitable solvent is selected on the basis whether the diastereomeric salt precipitates out differently. The separation of diastereomeric salt may result either spontaneously or by addition of cosolvent or salting out or evaporation of the solvent or addition of a cosolvent. Alternatively, the separation may result simply by stirring at a suitable temperature in a solvent(s) until one of the salts preferentially precipitate out. Purification of diastereomeric salt is possible by refluxing in a suitable solvent. The free base is liberated from its salt using a suitable base reagent. The diastereomeric salt is dissolved or suspended in a mixture of water and organic solvent and is neutralized with a base under stirring. Free base is obtained after separation of aqueous layer and evaporation of the organic solvent.
The solvents used during the resolution can include solvents or mixtures thereof such as (C1-C4) alcohol, (C1-C4)ketone, dimethylformamide, ethyl acetate, methyl acetate, methyl ethyl ketone, acetonitrile, propionitrile, THF, dioxane and the like; the solvent used optionally may contain water up to 5%, but presence of water or its amount is not critical. Suitable temperature range for the resolution includes temperature from 0xc2x0 C. to reflux temperature of the solvent used, preferably 0xc2x0 C. to 80xc2x0 C. The acid chiral reagents, which can be used to form a diastereomeric salt, include tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, lactic acid, maleic acid, amino acids and the like.
By repeated crystallization from a suitable solvent, the precipitated salt is enriched in the salt of dextrorotatory isomer of the desired diastereomer to yield a product of constant optical rotation.
Suitable base reagent for the hydrolysis of diastereomeric salt includes sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate in aqueous media at temperatures varying between 5xc2x0 C. to 25xc2x0 C.
Finally, the desired salt of compound of formula (II), (III), or (IV); or pharmaceutically acceptable salt of compound of formula (I) can be formed from the corresponding stereoisomer and a suitable acid. The optically pure (S)-(+) compound of formula (I), is converted into its bisulfate salt using sulfuric acid 70% to 98%, in an appropriate solvent at suitable temperature to afford (+)-Clopidogrel bisufate, polymorph I as desired.
Alternatively, the diastereomers formed may be separated by conventional methods of purification such as fractional crystallization, column chromatography and the like followed by cleavage of salt to give product of desired stereochemistry. It is preferable to use, such a chiral agent, which can selectively form diastereoisomer with either R or S stereoisomer of intermediate I, II, III or IV. The chiral reagent used may be in 0.5 to 1.1 molar ratio.
Determination of the enantiomeric purity of the (+)-dextrorotatory and (xe2x88x92)-laevorotatory enantiomers may be carried through proton NMR spectroscopy with the addition of a chiral rare earth reagents (shift reagents) or by HPLC using a chiral stationary phase as well as through measurement of optical rotation.
The absolute stereochemistry of the diastereomeric salt of II, III or IV compounds may be determined using conventional methods, such as X-ray crystallography. The absolute stereochemistry of chiral compounds can also be determined by comparing it with reference standards known in literature.
The pharmaceutically acceptable mineral and organic acid salts of optically active enantiomers of Clopidogrel are prepared using various acidic salts, which forms a part of this invention but are not limited to hydrogen sulfates, hydrohalides, taurocholates and the like.
More specifically the present process of invention results in Clopidogrel bisulfate of melting point 184xc2x13xc2x0 C., which is characteristic of Clopidogrel bisulfate form I. Alternatively, Clopidogrel bisulfate form II can also be prepared by known method (WO 99/65915, FR 98 07464).
The process of this invention also includes the process to recycle the unwanted stereoisomer through racemization. The conditions for racemization of all the intermediates of general formula II, III or IV as well as final product I, involves the similar solvent and catalyst in equimolar quantities. Suitable catalyst is generally a base such as LDA(Lithium diisopropylamide), KOH, NaOH, K+-t-BuOxe2x88x92, NaOMe, NaH, KH and the like. Suitable solvent used during the resolution can include solvents or mixtures thereof such as (C1-C4) alcohol, (C1-C4)ketone, ethyl acetate, methyl acetate, methyl ethyl ketone, THF, dioxane and the like; the solvent used optionally may contain water up to 5%. Suitable temperature range for the resolution includes temperature from 0xc2x0 C. to reflux temperature of the solvent used, preferably 0xc2x0 to 80xc2x0 C.
The process described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation to the scope of the invention.